Type II diabetes mellitus (T2DM) is a burgeoning epidemic in the United States. The number one cause of death in T2DM is cardiovascular disease (CVD). Our laboratory has generated transgenic mouse models to study the effects of loss and gain of function of glucose transporters on the development and progression of T2DM and CVD. Studies indicate that alterations in myocardial energy metabolism play a role in the etiology and progression of diabetic cardiomyopathy. We have shown that mice without the insulin responsive glucose transporter, GLUT4 (G4 Null), have hypertrophied hearts that unexpectedly take up more than normal amounts of glucose and exhibit increased glycolysis and glycogen synthesis. In vitro, G4 Null hearts also sustain less injury and regain more function than wild-type (WT) after ischemia/reperfusion (I/R). G4 Null mice show an increased expression of GLUT8, a new member of the glucose transporter family. Considering these results, transgenic mice overexpressing GLUT8 in the heart only (H8) have been generated to assess the role of GLUT8 in cardioprotection. The H8 mice exhibit significantly increased resistance to I/R damage compared to WT that is accompanied by upregulation of genes of both glucose of fatty acid metabolism. The central hypothesis of this proposal is that overexpression of GLUT8 with gain of function in the heart increases cardiac metabolic capacity as manifested by increases in both glucose and fatty acid utilization and glycogen storage. The H8 cardiac metabolic phenotype should enable the H8 heart to resist the deleterious effects of pathological systemic metabolism. It is expected that the H8 heart will maintain metabolic flexibility and resist injury and loss of function after I/R under conditions of systemic metabolic stress (i.e. high fat diet [HF]). Development of therapies that increase the expression of GLUT8 in the heart may help to attenuate the effects of diabetic cardiomyopathy. PUBLIC HEALTH RELEVANCE: The number one cause of death of diabetics is cardiovascular disease and glucose uptake and metabolism is compromised in these individuals. Preliminary studies in this proposal show that hearts overexpressing the GLUT8 glucose transporter are resistant to ischemic injury. The therapeutic potential of GLUT8 overexpression in diabetic models will be assessed in this proposal.